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ABSTRACT: For investigations into treatment of Parkinson's disease, the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated primate has become one of the most important and established animal models. Various species of both Old and New world primate have been used, employing differing MPTP-treatment regimes and methods for the assessment of motor defi cits and motor complications. In this chapter, we briefl y review the use of these varying models and treatment regimes, the effects of MPTP treatment and the general characteristics and drug response of the primate model. In detail, we describe the procedures we employ for MPTP treating the common marmoset including the specifi c welfare, husbandry and aftercare protocols that are essential to produce a successful model. We also describe the methods for inducing the expression of persistent dyskinesia and how to accurately assess changes in locomotor activity, motor disability
and the severity of dyskinesia.
�Key words: �MPTP , Primate , Common marmoset ,
01/2011: pages 371-400;
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ABSTRACT: Dopamine agonist treatment in early Parkinson's disease (PD) induces less dyskinesia than l-dopa. However, once dyskinesia has developed, dopamine agonists administered with l-dopa exacerbate involuntary movements. The dopamine partial D2/D3 agonist pardoprunox reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates without hyperactivity, indicating that pardoprunox may alleviate dyskinesia without compromising l-dopa's beneficial actions. This study examines a clinical scenario in which pardoprunox was introduced, in an l-dopa sparing strategy, to existing l-dopa treatment in MPTP-treated marmosets previously primed to express dyskinesia. l-Dopa (5-10 mg/kg) produced effects, which were stable over the 13 treatment days, of increased locomotor activity, reversed motor disability and marked dyskinesia. Pardoprunox (SLV308; 0.0125-0.025 mg/kg) plus l-dopa (3-10 mg/kg) administration increased locomotor activity over the same treatment period and initially produced an equivalent reversal of motor disability compared to l-dopa, however this effect was enhanced as treatment progressed. This reflected the prolonged duration of effect of pardoprunox compared to that of l-dopa. While pardoprunox plus l-dopa treatment initially produced dyskinesia to the same extent as l-dopa alone, the intensity diminished as treatment progressed and it was significantly different at the end of the study. On subsequent l-dopa challenge there was no difference in motor disability reversal between those animals previously treated with pardoprunox plus l-dopa compared to l-dopa alone but the combination treatment produced significantly less dyskinesia. These data suggest that pardoprunox may provide therapeutic benefit in mid to late stage PD by reducing dyskinesia while maintaining efficacy when used with concomitant l-dopa treatment.
Experimental Neurology 12/2010; 226(2):320-7. · 4.70 Impact Factor
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ABSTRACT: Partial D(2/3) dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease (PD) that may avoid common dopaminergic side-effects, including dyskinesia and psychosis. The present study focussed on the in vivo pharmacological and therapeutic characterisation of the novel D(2/3) receptor partial agonist and full 5-HT(1A) receptor agonist pardoprunox (SLV308; 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monochloride). Pardoprunox induced contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED=0.03mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED=0.03mg/kg; po) and decreased motor disability (MED=0.03mg/kg; po). The effects of pardoprunox were reversed by the D(2) antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED=0.01mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED=0.3mg/kg; po) and apomorphine-induced climbing (MED=0.6mg/kg; po) in rodents. Pardoprunox also induced 5-HT(1A) receptor-mediated behaviours, including flat body posture and lower lip retraction (MED=0.3mg/kg; po) and these were reversed by the 5-HT(1A) receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional DA D(2) receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD. The presence of functional 5-HT(1A) agonist activity might confer anti-dyskinetic activity and have effects that control neuropsychiatric components of PD.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 04/2010; 20(8):582-93. · 3.68 Impact Factor
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ABSTRACT: We previously showed that continuous infusion of rotigotine resulted in less dyskinesia than repeated pulsatile rotigotine administration or repeated oral administration of L-DOPA in MPTP-treated marmosets. Now we investigate whether continuous rotigotine delivery modifies established dyskinesia induced by prior exposure to repeated pulsatile administration of L-DOPA or rotigotine in MPTP-treated common marmosets. Repeated oral administration of L-DOPA or subcutaneous bolus administration of rotigotine over 28 days improved motor deficits but resulted in the onset of dyskinesia of moderate intensity. When these animals were switched to a 28-day continuous infusion of rotigotine, the reversal of motor disability was maintained. In those animals initially treated with L-DOPA, there was a small reduction in dyskinesia intensity but a significant reduction in the duration of dyskinesia. However, in animals initially treated with repeated bolus administration of rotigotine, dyskinesia intensity was significantly reduced. Initial treatment with a continuous infusion of rotigotine for 28 days reversed motor disability and resulted in a low incidence of dyskinesia. On switching to repeated oral administration of L-DOPA, the improvement in motor disability was maintained but the propensity of L-DOPA to provoke dyskinesia was not affected. In addition, while the continuous delivery of rotigotine prevented the expression of dyskinesia, the previously demonstrated ability of dopamine agonists to prime for dyskinesia could not be avoided. These data suggest that dyskinesia induced by pulsatile drug treatment may be improved by switching to continuous rotigotine delivery. In addition, while continuous delivery of rotigotine may prime for dyskinesia, it does not lead to its expression.
Experimental Neurology 10/2009; 221(1):79-85. · 4.70 Impact Factor
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ABSTRACT: Rotigotine is a novel, non-ergoline dopamine D(3)/D(2)/D(1)-receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of motor disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l-DOPA prevented l-DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l-DOPA was then co-administered for a further 28 days. Animals were assessed for locomotor activity, motor disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved motor deficits and normalized motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l-DOPA alone. The addition of l-DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l-DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l-DOPA from inducing dyskinesia suggesting that l-DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
Experimental Neurology 08/2009; 219(2):533-42. · 4.70 Impact Factor
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ABSTRACT: L-DOPA treatment of Parkinson's disease induces a high incidence of motor complications, notably dyskinesia. Longer acting dopamine agonists, e.g. ropinirole, are thought to produce more continuous dopaminergic stimulation and less severe dyskinesia. However, standard oral administration of dopamine agonists does not result in constant plasma drug levels, therefore, more continuous drug delivery may result in both prolonged reversal of motor deficits and reduced levels of dyskinesia. Therefore, we compared the effects of repeated oral administration of ropinirole to constant subcutaneous infusion in MPTP-treated common marmosets. Animals received oral administration (0.4 mg/kg, BID) or continuous infusion of ropinirole (0.8 mg/kg/day) via osmotic minipumps for 14 days (Phase I). The treatments were then switched and continued for a further 14 days (Phase II). In Phase I, locomotor activity was similar between treatment groups but reversal of motor disability was more pronounced in animals receiving continuous infusion. Dyskinesia intensity was low in both groups however there was a trend suggestive of less marked dyskinesia in those animals receiving continuous infusion. In Phase II, increased locomotor activity was maintained but animals switched from oral to continuous treatment showing an initial period of enhanced locomotor activity. The reversal of motor disability was maintained in both groups, however, motor disability tended towards greater improvement following continuous infusion. Importantly, dyskinesia remained low in both groups suggesting that constant delivery of ropinirole neither leads to priming nor expression of dyskinesia. These results suggest that a once-daily controlled-release formulation may provide improvements over existing benefits with standard oral ropinirole in Parkinson's disease patients.
Experimental Neurology 06/2008; 211(1):172-9. · 4.70 Impact Factor
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ABSTRACT: Most patients with Parkinson's disease (PD) develop dyskinesia and other motor complications after prolonged L-dopa use. We now report on the relationship between L-dopa dose and the duration and severity of dyskinesia in L-dopa-primed MPTP-treated primates with marked nigral degeneration mimicking late stage PD. With increasing doses of L-dopa, locomotor activity increased and motor disability declined. The duration of dyskinesia following L-dopa administration increased dose-dependently, and showed a linear correlation with total locomotor activity. In addition, the time-course of dyskinesia paralleled closely that of locomotor activity in a dose-dependent manner. In contrast, severity of dyskinesia showed a non-linear correlation with total locomotor activity, low doses of L-dopa eliciting severe dyskinesia for short periods of time. The threshold for dyskinesia induction and the antiparkinsonian effects of L-dopa appear very similar in primed MPTP primates mimicking late stage PD. Reducing individual doses of L-dopa to avoid severe dyskinesia can markedly compromise the antiparkinsonian response. Our results extend the relevance of the dyskinetic MPTP-treated primate in studying the genesis of involuntary movements occurring in L-dopa treated patients with PD.
Acta Neurovegetativa 10/2007; 114(9):1147-53. · 2.73 Impact Factor
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ABSTRACT: The level of leucine-rich repeat kinase 2 (Lrrk2) mRNA expression was measured by reverse transcription-polymerase chain reaction in anterior striatum from normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets (Callithrix jacchus) that had L-3,4-dihydroxyphenylalanine methyl ester (L-DOPA)-induced dyskinesia. The level of striatal Lrrk2 mRNA was increased in MPTP-treated common marmosets that had L-DOPA-induced dyskinesia compared with normal animals that did not receive l-DOPA. Marmosets that exhibited higher levels of dyskinesia had the greatest increase in striatal Lrrk2 mRNA. Lrrk2 mRNA expression was also measured in human striatum and substantia nigra from control subjects and patients dying with Parkinson's disease. In contrast to marmoset tissue, no alteration in Lrrk2 mRNA expression was found in parkinsonian human brain. However, the brain was from patients who had an overall low level of dyskinesia. The correlation between striatal Lrrk2 mRNA levels in MPTP-treated common marmoset striatum and L-DOPA-induced dyskinesia indicates that LRRK2 may have a role in the molecular alterations that cause L-DOPA-induced dyskinesia.
European Journal of Neuroscience 08/2007; 26(1):171-7. · 3.63 Impact Factor
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B-Y Zeng,
M M Iravani,
S-T Lin,
M Irifune,
M Kuoppamäki,
G Al-Barghouthy,
L Smith, M J Jackson,
S Rose,
A D Medhurst,
P Jenner
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ABSTRACT: Dysfunction of the ubiquitin-proteasome system occurs in the substantia nigra (SN) in Parkinson's disease (PD). However, it is unknown whether this is a primary cause or a secondary consequence of other components of the pathogenic process. We have investigated in nonhuman primates whether initiating cell death through mitochondrial complex I inhibition using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) altered proteasomal activity or the proteasomal components in the SN. Chymotrypsin-like, trypsin-like and peptidylglutamyl-peptide hydrolase (PGPH) activating of 20S proteasome were decreased in SN homogenates of MPTP-treated marmosets compared to naïve animals. Western blotting revealed a marked decrease in the expression of 20S-alpha subunits, but no change in 20S-beta subunits in the SN of MPTP-treated marmoset compared to naïve animals. There was a marked decrease in the expression of the proteasome activator 700 (PA700) and proteasome activator 28 (PA28) regulatory complexes. The 20S-alpha4 subunit immunoreactivity was decreased in the nucleus of colocalized tyrosine hydroxylase (TH)-positive cells of MPTP-treated animals compared to naïve animals but no difference in the intensity of 20S-beta1i subunit staining. Immunoreactivity for PA700-Rpt5 and PA28-alpha subunits within surviving TH-positive cells of MPTP-treated marmoset was reduced compared to naïve controls. Overall, the changes in proteasomal function and structure occurring follow MPTP-induced destruction of the SN in common marmosets were very similar to those found in PD. This suggests that altered proteasomal function in PD could be a consequence of other pathogenic processes occurring in SN as opposed to initiating cell death as previously suggested.
European Journal of Neuroscience 05/2006; 23(7):1766-74. · 3.63 Impact Factor
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ABSTRACT: l-3,4-dihydroxyphenylalanine methyl ester (l-DOPA)-induced dyskinesia in Parkinson's disease may result from aberrant glutamatergic stimulation of the striatum due to synaptic plasticity in the motor cortex or striatum as a consequence of adaptation of striatal output pathways. This might result from changes in NMDA receptor subunit or NMDA receptor associated postsynaptic density (PSD) scaffold protein expression. Using immunoautoradiography the expression levels of NR1 and NR2B subunits of the NMDA receptor and the postsynaptic density scaffold proteins, PSD-95, PSD-93, and neurofilament light (NFL) were examined in normal common marmosets (Callithrix jacchus) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals that exhibited high or low levels of l-DOPA-induced dyskinesia. Brains from MPTP-lesioned animals that were not primed for l-DOPA-induced dyskinesia were not included in this study. No alterations in the NR1 NMDA receptor subunit were observed. The NR2B NMDA receptor subunit was increased in caudal caudate nucleus and putamen, hippocampus, cingulate motor area (CMA), supplementary motor area (SMA) and dorsal primary motor cortex (dMI) of highly dyskinetic MPTP-lesioned marmosets, but not in animals with low levels of dyskinesia. PSD-93 was decreased in the globus pallidus of marmosets with high and low levels of dyskinesia and increased in the CMA, SMA and dMI of highly dyskinetic marmosets. PSD-95 was increased in the SMA of highly dyskinetic marmosets, but not in animals with low dyskinesia. NFL expression was elevated in the SMA and dorsal and ventral MI of highly dyskinetic marmosets. These results suggest that l-DOPA treatment of MPTP-lesioned marmosets can affect glutamatergic systems and indicate that altered NMDA receptor function may relate to dyskinesia.
European Journal of Neuroscience 07/2005; 21(12):3240-50. · 3.63 Impact Factor
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ABSTRACT: The potent and long acting D-1 receptor agonist, A-77636 reverses motor deficits in MPTP treated common marmosets following subcutaneous or oral administration. We now explore the effects of acute versus repeated administration of A-77636 and the relative roles of D-1 and D-2 receptor involvement in its antiparkinsonian actions. Acute oral administration (0.18-9.0 mg/kg) or subcutaneous administration (0.036-1.08 mg/kg) of A-77636 produced well co-ordinated bouts of discontinuous locomotor activity. There was no evidence of repetitive or stereotyped movements. However, oral administration of A-77636 (1.44 mg/kg) on alternate days for 10 days produced tolerance to the increase in locomotor activity and improvement of disability. Pretreatment with the D-1 antagonist SCH 23390 (0.625, 2.5 or 5.0 mg/kg, intraperitoneally), produced a dose dependent reduction in locomotor activity and antagonised the reduction in disability scores following administration of A-77636 (0.36 mg/kg, subcutaneously). The inhibitory effects of SCH 23390 lasted for some 2-5 hours after which the activity of A-77636 was gradually restored. Unexpectedly, pretreatment with the D-2 antagonist raclopride (1.25, 5.0 or 20.0 mg/kg, intraperitoneally), dramatically diminished the antiparkinsonian effects of A-77636 (0.36 mg/kg, subcutaneously) in a dose dependent manner. The dependence of the antiparkinsonian activity of A-77636 on intact D-2 receptor function, suggests a need for endogenous D-2 receptor tone to express D-1 mediated locomotor activity.
Acta Neurovegetativa 03/2002; 109(2):123-40. · 2.73 Impact Factor
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ABSTRACT: Sonic hedgehog (SHH) has trophic actions on dopaminergic cell cultures and protects them from MPP(+) toxicity but its in vivo actions have not been explored. We now investigate the effects of unilateral supranigral administration of SHH on nigro-striatal function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. SHH (0.1 or 1.0 microg) or vehicle was stereotaxically injected into the region of the right substantia nigra twice with an interval of 5 weeks between administrations. The first or second administration of low dose SHH (0.1 microg) did not significantly improve motor disability or locomotor activity compared to time-matched vehicle-treated animals. There was, however, an approximately 30% improvement in both motor disability and locomotor activity following the first administration of high dose SHH (1.0 microg). No further improvements occurred following the second high dose SHH treatment. Acute oral administration of L-3,4-dihydroxyphenylalanine (L-DOPA) produced a smaller increase in locomotor activity and greater reversal of motor disability in animals treated with SHH than occurred in vehicle-treated common marmosets. In the substantia nigra pars compacta, ipsilateral to SHH administration, the number of tyrosine hydroxylase-positive neurones was increased by 21% (P > 0.05) and 57% (P < 0.05) in low and high dose SHH groups respectively compared to the untreated contralateral hemisphere. There was no difference in the number of glial fibrillary acidic protein-positive cells. SHH may improve nigro-striatal function by restoring tyrosine hydroxylase positivity. This is reflected by an improvement in basal disability and a reduction in the lesion-induced response to L-DOPA.
Neuroscience 02/2002; 114(1):99-109. · 3.38 Impact Factor
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ABSTRACT: De novo administration of long-acting dopamine agonists, such as ropinirole, to patients with Parkinson's disease or to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated subhuman primates produces a lower incidence of dyskinesia than occurs with L-DOPA. This study compares the intensity of dyskinesia produced by combinations of L-DOPA and ropinirole and by these drugs alone, using the MPTP-treated common marmoset model of Parkinson's disease. The objective is to determine the optimum therapeutic strategy for the long-term control of Parkinson's disease with a minimal risk of dyskinesia. MPTP-treated marmosets received either L-DOPA alone, ropinirole alone, or one of two combinations of these drugs (either L-DOPA dominant or ropinirole dominant) daily for 28 days in doses titrated to produce a similar improvement in disability and increase in locomotion. In the group receiving L-DOPA alone, there was a trend for peak dose locomotor activity to increase and the duration of drug effect to decline over the period of the study. L-DOPA alone induced marked dyskinesia over the period of treatment, in contrast to ropinirole which produced a low intensity of involuntary movements. The L-DOPA dominant combination initially produced little dyskinesia, but this became increasingly intense as the study progressed. In contrast, the ropinirole dominant combination produced no greater intensity of dyskinesia than was produced by ropinirole alone. These data suggest that in early Parkinson's disease, the use of ropinirole alone or in combination with a low-dose L-DOPA might delay the induction of dyskinesias while improving motor performance.
Movement Disorders 08/2001; 16(4):631-41. · 4.51 Impact Factor
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ABSTRACT: Parkinson's disease (PD) is associated with a progressive loss of dopamine neurons in the substantia nigra and degeneration of dopaminergic terminals in the striatum. Although L-DOPA treatment provides the most effective symptomatic relief for PD it does not prevent the progression of the disease, and its long-term use is associated with the onset of dyskinesia. In rodent and primate studies, glial cell line-derived neurotrophic factor (GDNF) may prevent 6-OHDA- or MPTP-induced nigral degeneration and so may be beneficial in the treatment of PD. In this study, we investigate the effects of GDNF on the expression of dyskinesia in L-DOPA-primed MPTP-treated common marmosets, exhibiting dyskinesia. GDNF or saline was administered by two intraventricular injections, 4 weeks apart, to MPTP-treated, L-DOPA-treated common marmosets primed to exhibit dyskinesia. Prior to GDNF or saline administration, all animals displayed marked dyskinesia when treated with L-DOPA. GDNF administration produced a significant improvement in motor disability and, following the second injection of GDNF, a significant improvement in the locomotor activity was observed. Following the administration of L-DOPA there was a greater reversal of disability and a reduction in the intensity of L-DOPA-induced dyskinesia in GDNF-treated animals compared to saline-treated controls. However, there was no significant difference in L-DOPA's ability to increase locomotor activity between GDNF-treated and saline-treated animals. GDNF treatment caused a significant increase in the number of tyrosine hydroxylase-positive neurons in the substantia nigra, but no change in [(3)H]mazindol binding to dopamine terminals was found in the striatum of GDNF-treated animals compared to saline-treated controls. In GDNF-treated animals a small but significant reduction in enkephalin mRNA was observed in the caudate nucleus but not in the putamen or the nucleus accumbens. Substance P mRNA expression was equally reduced in the caudate nucleus and the putamen of the GDNF-treated animals but not in the nucleus accumbens. Intraventricular administration of GDNF improved MPTP-induced disability and reversed dopamine cell loss in the substantia nigra. GDNF also diminished L-DOPA-induced dyskinesia, which may relate to its ability to partly restore nigral dopaminergic transmission or to modify the activity of striatal output pathways.
European Journal of Neuroscience 03/2001; 13(3):597-608. · 3.63 Impact Factor
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ABSTRACT: The novel selective adenosine A(2A) receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with l-DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in motor disability. Coadministration of KW-6002 with a low dose of L-DOPA also produced an additive improvement in motor disability, and increased locomotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with L-DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate L-DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to L-DOPA. Selective adenosine A(2A) receptor antagonists, such as KW-6002, may be one means of reducing the dosage of L-DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.
Experimental Neurology 05/2000; 162(2):321-7. · 4.70 Impact Factor
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Y Kuwana,
S Shiozaki,
T Kanda,
M Kurokawa,
K Koga,
M Ochi,
K Ikeda,
H Kase, M J Jackson,
L A Smith,
R K Pearce,
P G Jenner
Advances in neurology 02/1999; 80:121-3.
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ABSTRACT: Treatment of Parkinson's disease with L-dopa therapy leads to long-term complications, including loss of drug efficacy and the onset of dyskinesia. Adenosine A2A receptors in striatum are selectively localized to GABAergic output neurons of the striato-pallidal pathway and may avoid such problems. The novel adenosine A2A receptor antagonist KW-6002 has been examined for antiparkinsonian activity in MPTP-treated primates. Oral administration of KW-6002 reversed motor disability in MPTP-treated common marmosets in a dose-dependent manner. However, KW-6002 only modestly increased overall locomotor activity and did not cause abnormal movement, such as stereotypy. The ability of KW-6002 to reverse motor disability was maintained on repeated daily administration for 21 days, and no tolerance was observed. KW-6002 induced little or no dyskinesia in MPTP-treated primates previously primed to exhibit dyskinesia by prior exposure to L-dopa. These results suggest that selective adenosine A2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.
Annals of Neurology 05/1998; 43(4):507-13. · 11.09 Impact Factor
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ABSTRACT: Rotigotine is a novel, non-ergoline dopamine D3/D2/D1-receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of motor disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l-DOPA prevented l-DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l-DOPA was then co-administered for a further 28 days. Animals were assessed for locomotor activity, motor disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved motor deficits and normalized motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l-DOPA alone. The addition of l-DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l-DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l-DOPA from inducing dyskinesia suggesting that l-DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
Experimental Neurology.
